Please use this identifier to cite or link to this item: http://192.168.1.35:80/jspui/handle/Hannan/31997
Title: Elabela/toddler is an endogenous agonist of the apelin APJ receptor in the adult cardiovascular system, and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension
Authors: Yang, P;Read, C;Kuc, RE;Buonincontri, G;Southwood, M;Torella, R;Upton, PD;Crosby, A;Sawiak, SJ;Carpenter, TA;Glen, RC;Morrell, NW;Maguire, JJ;Davenport, AP
subject: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
apelin
cardiopulmonary
Elabela/Toddler
pulmonary hypertension
receptors, G-protein-coupled
IMMUNOCYTOCHEMICAL LOCALIZATION
CARDIAC CONTRACTILITY
ENDOTHELIAL-CELLS
IN-VIVO
ELABELA
HEART
PATHWAY
Disease
LIGAND
Elabela/Toddler
apelin
cardiopulmonary
pulmonary hypertension
receptors, G-protein-coupled
Amino Acid Sequence
Animals
Apelin
Binding Sites
Catheterization
Disease Models, Animal
Down-Regulation
Endothelium, Vascular
Heart Ventricles
Humans
Hypertension, Pulmonary
Intercellular Signaling Peptides and Proteins
Male
Molecular Dynamics Simulation
Peptide Hormones
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Endothelium, Vascular
Heart Ventricles
Animals
Humans
Rats
Rats, Sprague-Dawley
Hypertension, Pulmonary
Disease Models, Animal
Peptide Hormones
Intercellular Signaling Peptides and Proteins
Catheterization
Down-Regulation
Binding Sites
Amino Acid Sequence
Protein Structure, Tertiary
Male
Molecular Dynamics Simulation
Clinical Sciences
Cardiovascular Medicine And Haematology
Public Health And Health Services
Cardiovascular System & Hematology
Year: 10-Mar-2017
Publisher: American Heart Association
Description: Background—Elabela/Toddler (ELA) is a critical cardiac developmental peptide that acts through the G protein-coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is down-regulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. Methods—In silico docking analysis, competition binding experiments and down-stream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using RT-qPCR, dual-labelling immunofluorescent staining and immunoassays. Acute cardiac effects of ELA-32 and [Pyr1]apelin-13 were assessed by magnet resonance imaging and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline (MCT) and Sugen/hypoxia exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the MCT rat model. Results—ELA competed for binding of apelin in human heart with overlap for the two peptides indicated by in silico modeling. ELA activated G protein- and Β-arrestin-dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, cardiac output and elicited vasodilatation in rat in vivo. ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in MCT exposed rats. Conclusions—These results show ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, is down-regulated in human disease and rodent PAH models and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in man.
URI: https://spiral.imperial.ac.uk:8443/handle/10044/1/44643
http://localhost/handle/Hannan/31997
Standard no: 0009-7322
https://dx.doi.org/10.1161/CIRCULATIONAHA.116.023218
Type Of Material: Article
Appears in Collections:Department of Surgery and Cancer

Files in This Item:
Click on the URI links for accessing contents.


Items in HannanDL are protected by copyright, with all rights reserved, unless otherwise indicated.